tbuckley/cabot-search huggingface dataset:
Epichaperome inhibition targets <i>TP53-</i>mutant AML and AML stem/progenitor cells
Authors: Bing Z. Carter, Po Yee Mak, Muharrem Muftuoglu, Wenjing Tao, Baozhen Ke, Jingqi Pei, Andrea D. Bedoy, Lauren B. Ostermann, Yuki Nishida, Sevinj Isgandarova, Mary Sobieski, Nghi Nguyen, Reid T. Powell, Margarita Martinez-Moczygemba, Clifford Stephan, Mahesh Basyal, Naveen Pemmaraju, Steffen Boettcher, Benjamin L. Ebert, Elizabeth J. Shpall, Barbara Wallner, Robert A. Morgan, Georgios I. Karras, Ute M. Moll, Michael Andreeff
Journal: Blood (2023)

TP 53-mutant acute myeloid leukemia (AML) remains the ultimate therapeutic challenge. Epichaperomes, formed in malignant cells, consist of heat shock protein 90 (HSP90) and associated proteins that support the maturation, activity, and stability of oncogenic kinases and transcription factors including mutant p53. High-throughput drug screening identified HSP90 inhibitors as top hits in isogenic TP53-wild-type (WT) and -mutant AML cells. We detected epichaperomes in AML cells and stem/progenitor cells with TP53 mutations but not in healthy bone marrow (BM) cells. Hence, we investigated the therapeutic potential of specifically targeting epichaperomes with PU-H71 in TP53-mutant AML based on its preferred binding to HSP90 within epichaperomes. PU-H71 effectively suppressed cell intrinsic stress responses and killed AML cells, primarily by inducing apoptosis; targeted TP53-mutant stem/progenitor cells; and prolonged survival of TP53-mutant AML xenograft and patient-derived xenograft models, but it had minimal effects on healthy human BM CD34+ cells or on murine hematopoiesis. PU-H71 decreased MCL-1 and multiple signal proteins, increased proapoptotic Bcl-2-like protein 11 levels, and synergized with BCL-2 inhibitor venetoclax in TP53-mutant AML. Notably, PU-H71 effectively killed TP53-WT and -mutant cells in isogenic TP53-WT/TP53-R248W Molm13 cell mixtures, whereas MDM2 or BCL-2 inhibition only reduced TP53-WT but favored the outgrowth of TP53-mutant cells. Venetoclax enhanced the killing of both TP53-WT and -mutant cells by PU-H71 in a xenograft model. Our data suggest that epichaperome function is essential for TP53-mutant AML growth and survival and that its inhibition targets mutant AML and stem/progenitor cells, enhances venetoclax activity, and prevents the outgrowth of venetoclax-resistant TP53-mutant AML clones. These concepts warrant clinical evaluation.
Discovering cellular programs of intrinsic and extrinsic drivers of metabolic traits using LipocyteProfiler
Authors: Samantha Laber, Sophie Strobel, Josep M Mercader, Hesam Dashti, Felipe R C Dos Santos, Phil Kubitz, Maya Jackson, Alina Ainbinder, Julius Honecker, Saaket Agrawal, Garrett Garborcauskas, David R Stirling, Aaron Leong, Katherine Figueroa, Nasa Sinnott-Armstrong, Maria Kost-Alimova, Giacomo Deodato, Alycen Harney, Gregory P Way, Alham Saadat, Sierra Harken, Saskia Reibe-Pal, Hannah Ebert, Yixin Zhang, Virtu Calabuig-Navarro, Elizabeth McGonagle, Adam Stefek, Josée Dupuis, Beth A Cimini, Hans Hauner, Miriam S Udler, Anne E Carpenter, Jose C Florez, Cecilia Lindgren, Suzanne B R Jacobs, Melina Claussnitzer
Journal: Cell Genomics (2023)

A primary obstacle in translating genetic associations with disease into therapeutic strategies is elucidating the cellular programs affected by genetic risk variants and effector genes. Here, we introduce LipocyteProfiler, a cardiometabolic-disease-oriented high-content image-based profiling tool that enables evaluation of thousands of morphological and cellular profiles that can be systematically linked to genes and genetic variants relevant to cardiometabolic disease. We show that LipocyteProfiler allows surveillance of diverse cellular programs by generating rich context- and process-specific cellular profiles across hepatocyte and adipocyte cell-state transitions. We use LipocyteProfiler to identify known and novel cellular mechanisms altered by polygenic risk of metabolic disease, including insulin resistance, fat distribution, and the polygenic contribution to lipodystrophy. LipocyteProfiler paves the way for large-scale forward and reverse deep phenotypic profiling in lipocytes and provides a framework for the unbiased identification of causal relationships between genetic variants and cellular programs relevant to human disease.
Successful kidney-alone transplantation in a patient with PH1 on combination RNA-interference therapy
Authors: Elisabeth L. Metry, Lisa J. Deesker, Sander F. Garrelfs, Michiel J.S. Oosterveld, Kerensa M. Beekman, Elisabeth A.M. Cornelissen, Linda Koster-Kamphuis, Jaap W. Groothoff
Journal: Kidney International (2023)
Brain tumors on slice: A novel platform for personalized therapeutic screening
Authors: Yusha Sun, Xin Wang, Guo-li Ming, Hongjun Song
Journal: Cell Reports Medicine (2023)

Mann and Zhang et al. developed a robust ex vivo slice culture platform consisting of resected patient high- and low-grade glioma tissue engrafted onto rat organotypic brain slices, and interrogated tumor responses to clinically relevant therapeutics with a novel treatment-response algorithm.
Maternal mortality, stillbirths, and neonatal mortality: a transition model based on analyses of 151 countries
Authors: Ties Boerma, Oona M R Campbell, Agbessi Amouzou, Cauane Blumenberg, Hannah Blencowe, Allisyn Moran, Joy E Lawn, Gloria Ikilezi
Journal: The Lancet Global Health (2023)

BackgroundMaternal mortality, stillbirths, and neonatal mortality account for almost 5 million deaths a year and are often analysed separately, despite having overlapping causes and interventions. We propose a comprehensive five-phase mortality transition model to improve analyses of progress and inform strategic planning.MethodsIn this empirical data-driven study to develop a model transition, we used UN estimates for 151 countries to assess changes in maternal mortality, stillbirths, and neonatal deaths. On the basis of ratios of maternal to stillbirth and neonatal mortality, we identified five phases of transition, in which phase 1 has the highest mortality and phase 5 has the lowest. We used global databases to examine phase-specific characteristics during 2000–20 for causes of death, fertility rates, abortion policies, health workforce and financing, and socioeconomic indicators. We analysed 326 national surveys to assess service coverage and inequalities by transition phase.FindingsAmong 116 countries in phases 1 to 4 in 2000, 73 (63%) progressed at least one phase by 2020, six advanced two phases, and three regressed. The ratio of stillbirth and neonatal deaths to maternal deaths increased from less than 10 in phase 1 to well over 50 in phase 4 and phase 5. Progression was associated with a declining proportion of deaths caused by infectious diseases and peripartum complications, declining total and adolescent fertility rates, changes in health-workforce densities and skills mix (ie, ratio of nurses or midwives to physicians) from phase 3 onwards, increasing per-capita health spending, and reducing shares of out-of-pocket health expenditures. From phase 1 to 5, the median coverage of first antenatal care visits increased from 66% to 98%, four or more antenatal care visits from 44% to 94%, institutional births from 36% to 99%, and caesarean section rates from 2% to 25%. The transition out of high-mortality phases involved a major increase in institutional births, primarily in lower-level health facilities, whereas subsequent progress was characterised by rapid increases in hospital births. Wealth-related inequalities reduced strongly for institutional birth coverage from phase 3 onwards.InterpretationThe five-phase maternal mortality, stillbirth, and neonatal mortality transition model can be used to benchmark the current indicators in comparison to typical patterns in the transition at national or sub-national level, identify outliers to better assess drivers of progress, and inform strategic planning and investments towards Sustainable Development Goal targets. It can also facilitate programming for integrated strategies to end preventable maternal mortality and neonatal mortality and stillbirths.FundingBill & Melinda Gates Foundation.
Ruxolitinib improves hematopoietic regeneration by restoring mesenchymal stromal cell function in acute graft-versus-host disease
Authors: Yan Lin, Quan Gu, Shihong Lu, Zengkai Pan, Zining Yang, Yapu Li, Shangda Yang, Yanling Lv, Zhaofeng Zheng, Guohuan Sun, Fanglin Gou, Chang Xu, Xiangnan Zhao, Fengjiao Wang, Chenchen Wang, Shiru Yuan, Xiaobao Xie, Yang Cao, Yue Liu, Weiying Gu, Tao Cheng, Hui Cheng, Xiaoxia Hu
Journal: Journal of Clinical Investigation (2023)

Acute graft-versus-host disease (aGVHD) is a severe complication of allogeneic hematopoietic stem cell transplantation. Hematopoietic dysfunction accompanied by severe aGVHD, which may be caused by niche impairment, is a long-standing clinical problem. However, how the bone marrow (BM) niche is damaged in aGVHD hosts is poorly defined. To comprehensively address this question, we used a haplo-MHC-matched transplantation aGVHD murine model and performed single-cell RNA-Seq of nonhematopoietic BM cells. Transcriptional analysis showed that BM mesenchymal stromal cells (BMSCs) were severely affected, with a reduction in cell ratio, abnormal metabolism, compromised differentiation potential, and defective hematopoiesis-supportive function, all of which were validated by functional assays. We found that ruxolitinib, a selective JAK1/2 inhibitor, ameliorated aGVHD-related hematopoietic dysfunction through a direct effect on recipient BMSCs, resulting in improved proliferation ability, adipogenesis/osteogenesis potential, mitochondria metabolism capacity, and crosstalk with donor-derived hematopoietic stem/progenitor cells. By inhibiting the JAK2/STAT1 pathway, ruxolitinib maintained long-term improvement of aGVHD BMSC function. Additionally, ruxolitinib pretreatment in vitro primed BMSCs to better support donor-derived hematopoiesis in vivo. These observations in the murine model were validated in patient samples. Overall, our findings suggest that ruxolitinib can directly restore BMSC function via the JAK2/STAT1 pathway and, in turn, improve the hematopoietic dysfunction caused by aGVHD.
Haploinsufficiency of NFKBIA reshapes the epigenome antipodal to the IDH mutation and imparts disease fate in diffuse gliomas
Authors: Markus Bredel, Lluís Espinosa, Hyunsoo Kim, Denise M Scholtens, Joseph P McElroy, Rajani Rajbhandari, Wei Meng, Thomas M Kollmeyer, Tathiane M Malta, Michael A Quezada, Griffith R Harsh, Teresa Lobo-Jarne, Laura Solé, Aran Merati, Surya Nagaraja, Sindhu Nair, Jaclyn J White, Nanda K Thudi, Jessica L Fleming, Amy Webb, Atsushi Natsume, Seishi Ogawa, Ruthild G Weber, Joan Bertran, S Jaharul Haque, Bettina Hentschel, C Ryan Miller, Frank B Furnari, Timothy A Chan, Anca-Ligia Grosu, Michael Weller, Jill S Barnholtz-Sloan, Michelle Monje, Houtan Noushmehr, Robert B Jenkins, C Leland Rogers, David R MacDonald, Stephanie L Pugh, Arnab Chakravarti
Journal: Cell Reports Medicine (2023)

Genetic alterations help predict the clinical behavior of diffuse gliomas, but some variability remains uncorrelated. Here, we demonstrate that haploinsufficient deletions of chromatin-bound tumor suppressor NFKB inhibitor alpha (NFKBIA) display distinct patterns of occurrence in relation to other genetic markers and are disproportionately present at recurrence. NFKBIA haploinsufficiency is associated with unfavorable patient outcomes, independent of genetic and clinicopathologic predictors. NFKBIA deletions reshape the DNA and histone methylome antipodal to the IDH mutation and induce a transcriptome landscape partly reminiscent of H3K27M mutant pediatric gliomas. In IDH mutant gliomas, NFKBIA deletions are common in tumors with a clinical course similar to that of IDH wild-type tumors. An externally validated nomogram model for estimating individual patient survival in IDH mutant gliomas confirms that NFKBIA deletions predict comparatively brief survival. Thus, NFKBIA haploinsufficiency aligns with distinct epigenome changes, portends a poor prognosis, and should be incorporated into models predicting the disease fate of diffuse gliomas.
Identification and targeting of protein tyrosine kinase 7 (PTK7) as an immunotherapy candidate for neuroblastoma
Authors: Jasmine Y. Lee, Hunter C. Jonus, Arhanti Sadanand, Gianna M. Branella, Victor Maximov, Suttipong Suttapitugsakul, Matthew J. Schniederjan, Jenny Shim, Andrew Ho, Kiran K. Parwani, Andrew Fedanov, Adeiye A. Pilgrim, Jordan A. Silva, Robert W. Schnepp, Christopher B. Doering, Ronghu Wu, H. Trent Spencer, Kelly C. Goldsmith
Journal: Cell Reports Medicine (2023)

GD2-targeting immunotherapies have improved survival in children with neuroblastoma, yet on-target, off-tumor toxicities can occur and a subset of patients cease to respond. The majority of neuroblastoma patients who receive immunotherapy have been previously treated with cytotoxic chemotherapy, making it paramount to identify neuroblastoma-specific antigens that remain stable throughout standard treatment. Cell surface glycoproteomics performed on human-derived neuroblastoma tumors in mice following chemotherapy treatment identified protein tyrosine kinase 7 (PTK7) to be abundantly expressed. Furthermore, PTK7 shows minimal expression on pediatric-specific normal tissues. We developed an anti-PTK7 chimeric antigen receptor (CAR) and find PTK7 CAR T cells specifically target and kill PTK7-expressing neuroblastoma in vitro. In vivo, human/murine binding PTK7 CAR T cells regress aggressive neuroblastoma metastatic mouse models and prolong survival with no toxicity. Together, these data demonstrate preclinical efficacy and tolerability for targeting PTK7 and support ongoing investigations to optimize PTK7-targeting CAR T cells for neuroblastoma.
We have a duty to promote disability inclusive refugee responses to achieve the highest attainable standard of health in the European region
Authors: Justine Gosling, Carrie Peterson, Marlee Quinn, Marco Tofani, Satish Mishra
Journal: BMJ (2023)

In 2021, the United Nations High Commissioner for Refugees (UNHCR) estimated that there were 27.1 million refugees globally. 1Refugees are people who have fled war, violence, conflict, or persecution and have crossed an international border to find safety in another country. 2 Often, refugees have had to flee with little more than the clothes on their back, leaving behind homes, possessions, jobs, and loved ones.
Why we need a global fund for health research
Authors: Kiran Raj Pandey, Bipin Adhikari
Journal: The Lancet Global Health (2023)

The 2002 institution of the Global Fund to Fight AIDS, Tuberculosis and Malaria—which has been able to channel US$70 billion to fund health services in low-income and middle-income countries (LMICs) thus far—was a seminal event in progressing towards a world with fewer health inequities. Now, it is time for an even bolder idea. We need to create a global fund for health research, and global health journals need to champion this idea.
Consequences of Using Post- or Prebronchodilator Reference Values in Interpreting Spirometry
Authors: Andrei Malinovschi, Xingwu Zhou, Anders Andersson, Helena Backman, Björn Bake, Anders Blomberg, Kenneth Caidahl, Maria J. Eriksson, Jonas Eriksson Ström, Viktor Hamrefors, Ola Hjelmgren, Christer Janson, Reza Karimi, David Kylhammar, Anne Lindberg, Eva Lindberg, Per Liv, Anna-Carin Olin, Adel Shalabi, C. Magnus Sköld, Johan Sundström, Hanan Tanash, Kjell Torén, Per Wollmer, Suneela Zaigham, Carl Johan Östgren, Jan E. Engvall
Journal: American Journal of Respiratory and Critical Care Medicine (2023)

Rationale: Postbronchodilator spirometry is used for the diagnosis of chronic obstructive pulmonary disease. However, prebronchodilator reference values are used for spirometry interpretation. Objectives: To compare the resulting prevalence rates of abnormal spirometry and study the consequences of using pre- or postbronchodilator reference values generated within SCAPIS (Swedish CArdioPulmonary bioImage Study) when interpreting postbronchodilator spirometry in a general population. Methods: SCAPIS reference values for postbronchodilator and prebronchodilator spirometry were based on 10,156 and 1,498 never-smoking, healthy participants, respectively. We studied the associations of abnormal spirometry, defined by using pre- or postbronchodilator reference values, with respiratory burden in the SCAPIS general population (28,851 individuals). Measurements and Main Results: Bronchodilation resulted in higher predicted medians and lower limits of normal (LLNs) for FEV1/FVC ratios. The prevalence of postbronchodilator FEV1/FVC ratio lower than the prebronchodilator LLN was 4.8%, and that of postbronchodilator FEV1/FVC lower than the postbronchodilator LLN was 9.9%, for the general population. An additional 5.1% were identified as having an abnormal postbronchodilator FEV1/FVC ratio, and this group had more respiratory symptoms, emphysema (13.5% vs. 4.1%; P < 0.001), and self-reported physician-diagnosed chronic obstructive pulmonary disease (2.8% vs. 0.5%, P < 0.001) than subjects with a postbronchodilator FEV1/FVC ratio greater than the LLN for both pre- and postbronchodilation. Conclusions: Pre- and postbronchodilator spirometry reference values differ with regard to FEV1/FVC ratio. Use of postbronchodilator reference values doubled the population prevalence of airflow obstruction; this was related to a higher respiratory burden. Using postbronchodilator reference values when interpreting postbronchodilator spirometry might enable the identification of individuals with mild disease and be clinically relevant.
The Prognostic Effect of Immune Cell Infiltration Depends on Molecular Subtype in Endometrioid Ovarian Carcinomas
Authors: Karolin Heinze, Evan S. Cairns, Shelby Thornton, Bronwyn Harris, Katy Milne, Marcel Grube, Charlotte Meyer, Anthony N. Karnezis, Sian Fereday, Dale W. Garsed, Samuel C.Y. Leung, Derek S. Chiu, Malak Moubarak, Philipp Harter, Florian Heitz, Jessica N. McAlpine, Anna DeFazio, David D.L. Bowtell, Ellen L. Goode, Malcolm Pike, Susan J. Ramus, C. Leigh Pearce, Annette Staebler, Martin Köbel, Stefan Kommoss, Aline Talhouk, Brad H. Nelson, Michael S. Anglesio
Journal: Clinical Cancer Research (2023)

Abstract Purpose: Endometrioid ovarian carcinoma (ENOC) is the second most-common type of ovarian carcinoma, comprising 10%–20% of cases. Recently, the study of ENOC has benefitted from comparisons to endometrial carcinomas including defining ENOC with four prognostic molecular subtypes. Each subtype suggests differential mechanisms of progression, although tumor-initiating events remain elusive. There is evidence that the ovarian microenvironment may be critical to early lesion establishment and progression. However, while immune infiltrates have been well studied in high-grade serous ovarian carcinoma, studies in ENOC are limited. Experimental Design: We report on 210 ENOC, with clinical follow-up and molecular subtype annotation. Using multiplex IHC and immunofluorescence, we examine the prevalence of T-cell lineage, B-cell lineage, macrophages, and populations with programmed cell death protein 1 or programmed death-ligand 1 across subtypes of ENOC. Results: Immune cell infiltrates in tumor epithelium and stroma showed higher densities in ENOC subtypes with known high mutation burden (POLEmut and MMRd). While molecular subtypes were prognostically significant, immune infiltrates were not (overall survival P &amp;gt; 0.2). Analysis by molecular subtype revealed that immune cell density was prognostically significant in only the no specific molecular profile (NSMP) subtype, where immune infiltrates lacking B cells (TILB minus) had inferior outcome (disease-specific survival: HR, 4.0; 95% confidence interval, 1.1–14.7; P &amp;lt; 0.05). Similar to endometrial carcinomas, molecular subtype stratification was generally superior to immune response in predicting outcomes. Conclusions: Subtype stratification is critical for better understanding of ENOC, in particular the distribution and prognostic significance of immune cell infiltrates. The role of B cells in the immune response within NSMP tumors warrants further study.
Pancreatic regional blood flow links the endocrine and exocrine diseases
Authors: Adam A. Rizk, Michael P. Dybala, Khalil C. Rodriguez, Marjan Slak Rupnik, Manami Hara
Journal: Journal of Clinical Investigation (2023)

An increasing number of studies have demonstrated that disease states of the endocrine or exocrine pancreas aggravate one another, which implies bidirectional blood flow between islets and exocrine cells. However, this is inconsistent with the current model of unidirectional blood flow, which is strictly from islets to exocrine tissues. This conventional model was first proposed in 1932, and it has never to our knowledge been revisited to date. Here, large-scale image capture was used to examine the spatial relationship between islets and blood vessels in the following species: human, monkey, pig, rabbit, ferret, and mouse. While some arterioles passed by or traveled through islets, the majority of islets had no association with them. Islets with direct contact with the arteriole were significantly larger in size and fewer in number than those without contact. Unique to the pancreas, capillaries directly branched out from the arterioles and have been labeled as "small arterioles" in past studies. Overall, the arterioles emerged to feed the pancreas regionally, not specifically targeting individual islets. Vascularizing the pancreas in this way may allow an entire downstream region of islets and acinar cells to be simultaneously exposed to changes in the blood levels of glucose, hormones, and other circulating factors.
Reviving the interest in the versatile drug nystatin: A multitude of strategies to increase its potential as an effective and safe antifungal agent
Authors: Filipa Sousa, Cecília Nascimento, Domingos Ferreira, Salette Reis, Paulo Costa
Journal: Advanced Drug Delivery Reviews (2023)

Nystatin is an antifungal molecule with a remarkable yet squandered versatility. In this review, its mechanism of action is explored, along with its extensive action spectrum and toxicity. A multitude of methodologies to tackle the drug's physical and chemical hurdles are outlined along with some proven-effective strategies to increase its activity and/or decrease its toxicity. A separate detailed section focused on micro and nanotechnology solutions addresses new drug delivery systems made of polymeric, metallic or lipid materials. Although the topical route depicts greater representativeness amongst these formulations, the intravenous, dental, oral, vaginal and inhalation routes are also mentioned. The unsuccessful previous attempts at developing parenteral formulations of nystatin or even the withdrawal of a nystatin-loaded multilamellar liposome should not divert research away from this drug. In fact, the interest in nystatin ought to be reawakened with the ongoing clinical trials on the promising nystatin-like genetically engineered derivate BSG005.
Pregnancy, pregnancy outcomes, and infant growth and development after recovery from Ebola virus disease in Liberia: an observational cohort study
Authors: Mosoka P Fallah, Cavan Reilly, Collin Van Ryn, Moses Badio, Sia Wata Camanor, Stephen G Kaler, Billy Johnson, Romeo Orone, Hilary Flumo, Soka J Moses, Kumblytee L Johnson, Nowiah Gorpudolo, Dehkontee Gayedyu-Dennis, Bonnie Dighero-Kemp, John Fayiah, Lindsay Marron, Lisa E Hensley, Robert J Taylor, Elizabeth S Higgs, H Clifford Lane, James D Neaton, Michael C Sneller
Journal: The Lancet Global Health (2023)

Minimal data exist on pregnancy following recovery from Ebola in people of child-bearing potential (females aged roughly 18-45 years). The aim of this study was to assess viral persistence or reactivation in pregnancy, the frequency of placental transfer of anti-Ebola IgG antibodies, and pregnancy outcomes in this population.